A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells

Tissue-derived adenosine, acting via the adenosine A(2A) receptor (A(2A)R), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A(2A)R stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A(2A)R engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A(2A)R stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-beta. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. In this regard, A(2A)R agonists fail to prevent autoimmunity by LAG-3(-/-) clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A(2A)R to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.     

Penicillin susceptibility breakpoints for Streptococcus pneumoniae and their effect on susceptibility categorisation in Germany (1997–2013)

Continuous nationwide surveillance of invasive pneumococcal disease (IPD) was conducted in Germany. From July 1, 1997, to June 30, 2013, data on penicillin susceptibility were available for 20,437 isolates. 2,790 of these isolates (13.7 %) originate from patients with meningitis and 17,647 isolates (86.3 %) are from non-meningitis cases. A slight decline in isolates susceptible at 0.06 and 0.12 μg/ml can be noticed over the years. Overall, 89.1 % of the isolates had minimum inhibitory concentrations (MICs) of ≤0.015 μg/ml. In 2012/2013, the first three isolates of Streptococcus pneumoniae with MICs of 8 μg/ml were found. The application of different guidelines with other MIC breakpoints for the interpretation of penicillin resistance leads to differences in susceptibility categorisation. According to the pre-2008 Clinical and Laboratory Standards Institute (CLSI) interpretive criteria, 5.3 % of isolates overall were intermediate and 1.4 % were resistant to penicillin. Application of the 2008–2014 CLSI interpretive criteria resulted in 7.6 % resistance among meningitis cases and 0.5 % intermediate resistance in non-meningitis cases. Referring to the 2009–2014 European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 7.6 % of the isolates in the meningitis group were resistant to penicillin. In the non-meningitis group, 6.1 % of the isolates were intermediate and 0.5 % were resistant. These differences should be kept in mind when surveillance studies on pneumococcal penicillin resistance are compared.     

Catheter-Associated Urinary Tract Infection by Pseudomonas aeruginosa Is Mediated by Exopolysaccharide-Independent Biofilms

Pseudomonas aeruginosa is an opportunistic human pathogen that is especially adept at forming surface-associated biofilms. P. aeruginosa causes catheter-associated urinary tract infections (CAUTIs) through biofilm formation on the surface of indwelling catheters. P. aeruginosa encodes three extracellular polysaccharides, PEL, PSL, and alginate, and utilizes the PEL and PSL polysaccharides to form biofilms in vitro; however, the requirement of these polysaccharides during in vivo infections is not well understood. Here we show in a murine model of CAUTI that PAO1, a strain harboring pel, psl, and alg genes, and PA14, a strain harboring pel and alg genes, form biofilms on the implanted catheters. To determine the requirement of exopolysaccharide during in vivo biofilm infections, we tested isogenic mutants lacking the pel, psl, and alg operons and showed that PA14 mutants lacking these operons can successfully form biofilms on catheters in the CAUTI model. To determine the host factor(s) that induces the ΔpelD mutant to form biofilm, we tested mouse, human, and artificial urine and show that urine can induce biofilm formation by the PA14 ΔpelD mutant. By testing the major constituents of urine, we show that urea can induce a pel-, psl-, and alg-independent biofilm. These pel-, psl-, and alg-independent biofilms are mediated by the release of extracellular DNA. Treatment of biofilms formed in urea with DNase I reduced the biofilm, indicating that extracellular DNA supports biofilm formation. Our results indicate that the opportunistic pathogen P. aeruginosa utilizes a distinct program to form biofilms that are independent of exopolysaccharides during CAUTI.     

Museum specimens reveal loss of pollen host plants as key factor driving wild bee decline in The Netherlands

Evidence for declining populations of both wild and managed bees has raised concern about a potential global pollination crisis. Strategies to mitigate bee loss generally aim to enhance floral resources. However, we do not really know whether loss of preferred floral resources is the key driver of bee decline because accurate assessment of host plant preferences is difficult, particularly for species that have become rare. Here we examine whether population trends of wild bees in The Netherlands can be explained by trends in host plants, and how this relates to other factors such as climate change. We determined host plant preference of bee species using pollen loads on specimens in entomological collections that were collected before the onset of their decline, and used atlas data to quantify population trends of bee species and their host plants. We show that decline of preferred host plant species was one of two main factors associated with bee decline. Bee body size, the other main factor, was negatively related to population trend, which, because larger bee species have larger pollen requirements than smaller species, may also point toward food limitation as a key factor driving wild bee loss. Diet breadth and other potential factors such as length of flight period or climate change sensitivity were not important in explaining twentieth century bee population trends. These results highlight the species-specific nature of wild bee decline and indicate that mitigation strategies will only be effective if they target the specific host plants of declining species.Pollinating insects such as bees play an essential role in the pollination of wild plants (1) and crops (2). However, reported population declines in both wild and managed bees (3–5) have raised concerns about loss of pollination services and triggered interest in identifying the underlying causes for bee decline (6). Land use change and agricultural intensification are major drivers of biodiversity loss in general (7, 8) and are considered the most important environmental drivers of loss of wild bee diversity in particular (6, 9). It is generally believed that these drivers affect bees, which depend on floral resources in both their larval and adult life stages, through repercussions on the availability of floral resources in contemporary anthropogenic landscapes (9–11), but, so far, scientific evidence that loss of floral resources is driving bee decline is lacking. Nevertheless, current strategies to mitigate bee decline focus primarily on enhancing floral resources (12). To prioritize and develop effective mitigation strategies, it is essential to identify the mechanisms underlying bee population trends and assess whether these are mediated by floral resources.Although bees as a group are declining, individual species show more variable responses, with some species declining sharply while others remain stable or even increase under current land use change and agricultural intensification (3, 4, 13). These differential responses can be used to disentangle the effects of floral resource availability from those of other potential factors affecting bee population trends. The proportion of the floral resources in contemporary anthropogenic landscapes that can be used for forage by a bee species depends on its diet breadth and host plant preference, and it may be expected that species that have declined have a narrower diet breadth and prefer host plants that have declined (14, 15). However, diet breadth and host plant preference of bee species is difficult to assess. Presently observed host plant use does not necessarily reflect actual preference, as preferred host plants may have gone locally extinct and bees that have declined may have become restricted in their food choice in their remaining habitats (15). In addition, if host plant use is measured for more individuals of abundant, widespread species than for rare ones, an apparent link between diet breadth and population trend may simply arise as a sampling artifact (16). Furthermore, the relationship between host plant use and population trend may be confounded by species’ rarity prior to the onset of major environmental changes (17), as rarity in itself increases susceptibility to stochastic events (18) and has been shown to be one of the most important factors predicting population decline in various taxa (19–21). Surprisingly, to our knowledge, none of the studies that have so far examined the relationship between diet breadth and/or host plant preference and bee population trends have taken species’ initial rarity into account (e.g., refs. 3, 4, 15, and 22). Other factors, such as body size (4, 23), phenology (4, 22), and sensitivity to climate change (4, 24, 25) may be associated with bee decline as well, and, to date, the relative importance of diet breadth and pollen host plant preference in explaining bee population trends remains unclear.Here we solve this problem by analyzing historical pollen preferences of wild bees (15). Bees are generally more selective in their choice of food plants when foraging for pollen (source of protein and minerals for both larvae and adults) than nectar (source of energy) (26, 27). Distributional changes in plant species from which pollen is collected therefore probably exerts a larger influence on bee populations than changes in nectar plants. We investigate whether and to what extent loss of preferred floral resources drives bee population trends in The Netherlands, one of the most human-modified and intensively farmed countries in the world. Over the course of the twentieth century, agriculture has intensified in The Netherlands (Fig. S1) and the area of seminatural habitat preferred by bees has diminished to only one-fifth of the area at the beginning of the twentieth century (Fig. S2). More than half of the bee species are currently on the national Red List (28). As such, this country is a particularly suitable study area to identify critical factors associated with bee population decline.We assessed pollen host plant use of bee species independently from their population trends by analyzing pollen loads on the bodies of bee specimens that were collected before 1950 (15), before the onset of agricultural intensification in The Netherlands. Altogether, our analysis included trend and trait data of 57 bee species in 10 genera and 4 subfamilies (Table S1). We calculated population trend indices for bee species and their host plants (period 1902–1949 vs. 1975–1999) using extensive national species distribution datasets (13, 29). Linear mixed models, with bee subfamily as a random factor to account for phylogeny, and a multimodel inference approach were used to examine the relationship between bee population trends and pollen host plant use, simultaneously taking into account differences in species’ rarity before the onset of agricultural intensification and other factors that have been proposed to explain bee population trends.     

Recommendations in the event of a suspected transfusion-related acute lung injury (TRALI)

The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.     

Goal-oriented cognitive rehabilitation for an individual with Mild Cognitive Impairment: Behavioural and neuroimaging outcomes

An individual, goal-oriented cognitive rehabilitation intervention was conducted with AB, a 77-year-old woman with MCI. Outcomes were evaluated using a client-centred measure of goal achievement and an experimental associative learning task testing a skill practised in the intervention. Pre- and post-intervention fMRI scans were compared to examine changes in brain activation. Following intervention, AB showed improved performance on rehabilitation goals and on the associative learning task. There were significant decreases in brain activation in sensory areas and significant increases in memory-related areas. Both client-centred measures and fMRI may assist in detecting clinically-meaningful changes resulting from cognitive rehabilitation interventions.